Kainate receptors (KARs) are a family of glutamate receptors whose activation leads to seizures in the hippocampus. KARs also modulate synaptic transmission and mediate long-term plasticity at a number of brain synapses. In CA3 pyramidal cells in the hippocampus, KARs are localized to one particular excitatory synapse-those formed by mossy fiber inputs from granule cells. KARs at mossy fiber synapses underlie an postsynaptic current (KA-EPSC) and play a role in the induction of long- and short-term potentiation of synaptic strength. The objective of these experiments is to determine the mechanisms by which KAR activation leads to altered synaptic strength and action potential firing patterns in hippocampal CA3 pyramidal neurons. These questions will be examined with a physiological approach that utilizes selective pharmacological compounds as well as gene-targeted mice lacking one or more KAR subunits. In Specific Aim 1, the cellular mechanisms that shape mossy fiber KA-EPSCs will be examined by analyzing their properties while altering synaptic strength or activating second messenger systems. These experiments will further understanding of the distinct physiological roles that mossy fiber KARs subserve, which will be integral for elucidating the role of KAR5 in hippocampal circuitry. In Specific Aim 2, we will determine the critical receptor subunits and physiological processes that lead from activation of mossy fiber KARs to synchronized neuronal firing patterns. We will test if changes in firing properties arise from non-ionic mechanisms, perhaps G-protein-mediated, or a particularly close association between KARs and ion channels involved in action potential initiation. In Specific Aim 3 we will establish the role of KARs involved in synaptic plasticity at excitatory synapses on CA3 pyramidal neurons. KARs were recently implicated in the induction of long-term potentiation (LTP) at mossy fiber synapses. We will extend our studies by examining the function of presynaptic KARs and determining the subunits underlying LTP using gene-targeted mice that lack one or more KAR subunits. The role of KARs in other forms of mossy fiber plasticity will also be investigated.